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At least 109 records · Page 6Linked to original sources
PubMed2000

Evidence against a direct cytotoxic effect of alpha interferon and zidovudine in HTLV-I associated adult T cell leukemia/lymphoma.

The combination of the anti-viral agents, zidovudine (AZT) and interferon-alpha (IFN), is a potent treatment of HTLV-I-associated adult T cell leukemia/lymphoma (ATL). In this study we investigate the possible mechanism of action of this combination by examining several cellular parameters including cell proliferation, cell cycle distribution and apoptosis. The ATL-derived T cell lines HuT-102 and MT-2 served as models. HTLV-I negative T cell lines (CEM and Jurkat) were used as controls. No significant modification of cell growth was observed except at suprapharmacological doses of AZT and IFN. Moreover, these effects were less pronounced in HTLV-I-infected cell lines compared to control cell lines. AZT and IFN treatment did not induce any significant modification of the expression of bcl-2 and p53. Interestingly no in vitro cytotoxic effect of AZT/IFN combination was observed on fresh leukemic cells derived from an acute ATL patient at diagnosis despite achievement of in vivo complete remission using the same therapy. These results suggest that the therapeutic effect of AZT and IFN is not through a direct cytotoxic effect of these drugs on the leukemic cells.

Aged↗
PubMed1998

Multiplex PCR for TCR delta rearrangements: a rapid and specific approach for the detection and identification of immature and mature rearrangements in ALL.

The preferential occurrence of immature T-cell receptor (TCR) delta rearrangements (i.e. incomplete Ddelta2-Ddelta3 and Vdelta2-Ddelta3) in B-cell precursor acute lymphoblastic leukaemia (BCP ALL) and of predominantly mature rearrangements (incomplete Ddelta2-Jdelta1, complete Vdelta1, Vdelta2, Vdelta3 to Jdelta1) in T-lineage ALL prompted us to establish two separate multiplex PCR systems for the identification of clonal TCRdelta rearrangements. PCR products of the expected size for the specific rearrangements were detectable from a dilution of 100-1000 clonal cells in 150000 polyclonal cells. Both multiplex PCR systems were used to analyse samples from 86 childhood BCPALLs and 30 T-lineage ALLs. The results of the multiplex PCRs were controlled by standard PCR analyses for the individual rearrangements and Southern blots, which were identical. Only immature TCRdelta rearrangements were detected in BCP ALL (59%), whereas no rearrangement was found in the remaining BCP leukaemias, thus confirming the exclusive presence of immature TCRdelta rearrangements in B-lineage cells. 50% of the T-lineage ALLs contained mature rearrangements, but no immature rearrangements were found. These two multiplex PCR techniques appear to be reliable and fast aids in the analysis of clonal TCRdelta rearrangements in ALL.

Blotting, Southern↗
PubMedDate not supplied

Positive selection of autologous peripheral blood stem cells.

The development of monoclonal antibodies against differentiation antigens on human haematopoietic cells has led to a new concept in stem cell purification: the positive selection. In terms of autologous PBSC transplantation, the immature stem cells are identified by their expression of a specific antigen, the CD34. The CD34 antigen is expressed on early lymphohaematopoietic stem cells and progenitor cells, but not on mature blood cells or on tumour cells of several diseases. CD34+ cells are found in low numbers in bone marrow (<2%) and in even lower numbers in steady state blood (<0.01%) but may increase from 1 to 5% after mobilization using chemotherapy and/or growth factors. Several techniques have been set up to enrich PBSC grafts in CD34+ stem cells. The quality of each system is here analysed in terms of CD34 purity of the selected cell fraction, the CD34 cell recovery, the tumour cell depletion efficiency and the functional capacity ex vivo and in vivo of the selected cells. The final CD34+ cell purity of the selected fractions is correlated to the concentration of CD34+ cells before selection. The optimal recoveries and the highest purities were generally obtained when the initial CD34 content was roughly over 1%. Below this figure, the final purity seems to be less predictable. Besides the better tolerance resulting from the reduction in the number of autologous cells, and consequently the total volume of DMSO reinfused to the patient, the selective enrichment of the CD34 cell population offers a new approach to tumour purging. The procedure by itself results in elimination of about 99% in the total number of initial cells, thus allowing reduction of the overall tumour cell number in the final autograft. However, its major interest is that, in diseases where tumour cells do not express the CD34 antigen, it is theoretically able to completely eliminate the tumour contamination of the graft. Based on previous data showing that lymphoma, myeloma, neuroblastoma and breast cancer cells are not CD34+, pilot clinical trials for the separation and transplantation of CD34+ cells selected from PBSC of patients with these diseases have recently been conducted. The efficacy of CD34 selection in reducing the tumour load of the PBSC of patients with these diseases has been reported. However, the efficacy of purging may greatly differ between individual patients, and complete eradication of contaminating cells from PBSC grafts was not always reached. There is now evidence that purified CD34+ cells are capable of supporting haematopoietic reconstitution in autologous transplantation. However, until now no study has demonstrated clear evidence that the reduction of tumour cells from PBSC of patients by CD34+ cell selection resulted in a lower relapse rate post-transplant, as compared to unselected PBSC infusion.

Antigens, CD34↗
PubMed1997

The Na+/H+ antiporter potentiates growth and retinoic acid-induced differentiation of P19 embryonal carcinoma cells.

The Na+/H+ exchanger is a ubiquitous plasma membrane protein that is responsible for pH regulation and is activated by growth factors. We examined the role of the Na+/H+ exchanger in cell growth and differentiation. Treatment of P19 cells with the Na+/H+ exchanger inhibitor Hoe 694 eliminated retinoic acid-induced differentiation in this cell line. We developed a P19 embryonal carcinoma cell line that was deficient in the Na+/H+ antiporter. Na+/H+ exchanger-deficient cells were reduced in the rate of cell growth and this effect was enhanced by the removal of added HCO3- and by reducing extracellular pH. The antiporter-deficient cells were also markedly deficient in their ability to differentiate to neuronal-like cells and recovered this ability when the Na+/H+ antiporter was reintroduced. The results show that the absence of Na+/H+ antiport as a pH regulatory mechanism can result in deficiencies in both cell growth and differentiation in embryonal carcinoma cells.

Animals↗
PubMed2005

Clonogenic growth patterns correlate with chemotherapy response in acute myeloid leukaemia.

Cytosine arabinoside and anthracycline-containing regimens induce remission in upwards of 60% of previously untreated patients with adult acute myeloid leukaemia (AML). Despite this, in addition to primary drug resistance, the majority of these patients relapse. Reliable methods for uniformly recognising these two subgroups at presentation do not exist and therefore a further attempt has been made to relate in vitro toxicity, using a clonogenic assay, to clinical outcome. In 10 normal controls and 12 chemotherapy naïve cases, mononuclear cells harvested by density gradient separation were re-suspended at a concentration of 2 x 10(5)/ml and quadruplicates of 250 microl per well cultured in methycellulose containing foetal calf serum and phytohaemagglutinin stimulated leucocyte conditioned medium. Cell kill was determined for cytosine arabinoside, daunorubicin and etoposide either singly or in combination using both a pulsed and continuous exposure. Aggregates were scored after seven days and three distinct patterns recognised. The patients all received the same drugs in a standard protocol and achievement of complete remission correlated with growth pattern. The survival of normal marrow colony-forming cells or GM-CFUc and the leukemic equivalent designated L-CFUc were assessed and a sensitivity index (SI) determined as a ratio of these two values in which more reproducible results were found when the drug was continuously present. It is concluded that the microculture technique is feasible and clearly demonstrates chemotherapy effect but no correlation was demonstrated with clinical outcome. This is a negative pilot study and, as a means of recognising drug sensitivity or resistance, should be discarded in favour of currently available molecular techniques.

Adolescent↗
PubMed2006

TRAIL, caspases and maturation of normal and leukemic myeloid precursors.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a membrane-bound cytokine molecule that belongs to the family of tumor necrosis factor (TNF). Members of this family share diverse biological effects, including induction of apoptosis and/or promotion of cell survival. Identification of TRAIL has generated considerable enthusiasm for its ability to induce apoptotic cell death in a variety of tumor cells, by engaging the death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5, while sparing most normal cells. Beside its anticancer activity, several studies have suggested a role for endogenously expressed TRAIL in hemopoiesis. In this review, we summarize the knowledge about the different lineage-specific roles of TRAIL and its receptors in hemopoiesis regulation. Moreover, the complex interplay among the signaling pathways triggered by TRAIL/TRAIL-receptors in myeloid cells is discussed in some detail.

Apoptosis↗
PubMed2006

Molecular analysis of the Imatinib-induced complete cytogenetic response in chronic myelogenous leukemia.

The aim of this study was to elucidate the relationship between clonal and normal haematopoiesis in chronic myelogenous leukemia (CML). Thirteen female patients who reached complete cytogenetic response (CCR) after Imatinib treatment were studied. Although all the study patients exhibited a polyclonal pattern of X inactivation, p210 BCR/ABL transcript remained detectable in all cases by nested RT-PCR. This study also demonstrated the presence of p190 transcript in nine out of 13 study patients. A longer follow-up analysis is needed to clarify the prognostic value of these results. The recent observation that clonal cytogenetic abnormalities may occur in CML patients in polyclonal remission after imatinib suggests that a neoplastic stem cell lacking BCR/ABL rearrangement may acquire further cytogenetic alterations other than Philadelphia chromosome.

Adult↗
PubMed2005

Tumorigenicity issues of embryonic carcinoma-derived stem cells: relevance to surgical trials using NT2 and hNT neural cells.

Cell therapy is a rapidly moving field with new cells, cell lines, and tissue-engineered constructs being developed globally. As these novel cells are further developed for transplantation studies, it is important to understand their safety profiles both prior to and posttransplantation in animals and humans. Embryonic carcinoma-derived cells are considered an important alternative to stem cells. The NTera2/D1 teratocarcinoma cell-line (or NT2-N cells) gives rise to neuron-like cells called hNT neurons after exposure to retinoic acid. NT2 cells form tumors upon transplantation into the rodent. However, when the NT2 cells are treated with retinoic acid to produce hNT cells, they terminally differentiate into post-mitotic neurons with no sign of tumorigenicity. Preliminary human transplantation studies in the brain of stroke patients also demonstrated a lack of tumorigenicity of these cells. This review focuses on the use of hNT neurons in cell transplantation for the treatment in central nervous system (CNS) diseases, disorders, or injuries and on the mechanism involved in retinoic acid exposure, final differentiation state, and subsequent tumorigenicity issues that must be considered prior to widespread clinical use.

Cell Culture Techniques↗
PubMed1993

Transcriptional repression by the Rb-related protein p107.

The transcription factor DRTF1/E2F is believed to play an important role in regulating cellular proliferation because it undergoes a series of periodic interactions with proteins that are known to be important regulators of the cell cycle, including the retinoblastoma gene product (pRb) and cyclin A. Furthermore, certain viral oncogene products, such as adenovirus E1a, disrupt these DRTF1/E2F complexes by sequestering the associated proteins. p107, a protein that is structurally related to pRb, also binds to DRTF1/E2F, and in this study we investigate the functional consequences of this interaction. We show that p107 can repress E2F binding site-dependent transcription and that the adenovirus E1a protein overcomes p107-mediated transcriptional repression. Two distinct but related proteins, pRb and p107, can therefore repress transcription driven by DRTF1/E2F, whereas the E1a protein overrides the repression. We also demonstrate that the transcription repressing properties of p107 and pRb are influenced by the cell type and by differentiation, because neither protein affects transcription in F9 embryonal carcinoma (EC) cells but both do so efficiently in differentiated derivatives. In this respect, the repressing activities of pRb and p107 inversely correlate with the presence of the cellular E1a-like activity previously documented in F9 EC cells. These data suggest that p107 and pRb exert their biological activities in some but not all cell types.

Adenovirus E1A Proteins↗
PubMed2001

Neuroendocrine differentiation in human prostate cancer. Morphogenesis, proliferation and androgen receptor status.

BACKGROUND: The frequent occurrence of neuroendocrine (NE) differentiation in common prostatic malignancies has attracted increasing attention in contemporary prostate cancer research. METHODS: The present review focuses on growth properties and the androgen receptor (AR) status of NE phenotypes, and discusses their morphogenetic origin in benign and malignant prostate tissue. RESULTS: Recent data have documented a phenotype link between NE cells and other cell lineages encountered in benign and malignant prostate tissue. NE tumor cells (as defined by the most commonly used endocrine marker chromogranin A) do not proliferate or show apoptotic activity. This particular phenotype also lacks the nuclear AR in both benign and malignant conditions. CONCLUSIONS: Prostatic NE cells most likely derive from local stem cells and represent terminally differentiated and androgen-insensitive cell populations in benign prostate tissue. The frequent occurrence of NE differentiation in prostatic adenocarcinoma obviously reflects the differentiation repertoire of its stem cells. Neoplastic NE cells devoid of nuclear AR constitute an androgen-insensitive cell population in prostate cancer. The absence of proliferative and apoptotic activity may endow NE tumor cells with relative resistance towards cytotoxic drugs and radiation therapy.

Androgens↗
PubMed1997

Irreversible cytotoxic effect of a novel lowly immunosuppressive antitumor fluorouridine derivative, UK-21.

Previously, we reported that the 5-fluorouridine derivative, 2',3',5'-tris-O-[N(2-n-propyl-n-pentanoylglycyl]-5-fluorouridine (UK-21), is a newly synthesized lowly immunosuppressive and potent antitumor drug in comparison with other fluorouridine derivatives such as 5-fluorouracil (5-FU), 5-fluorouridine (5-FUR) and 5-fluorodeoxyuridine (5-FUDR). In order to elucidate the molecular mechanism of antitumor activity of UK-21, we compared the effect of the four drugs on cell proliferation, cell cycle progression and macromolecular syntheses. When KB cells were subjected to a colony-forming inhibition assay designed to expose the cells to the drugs for 4-96 h and wash out, UK-21 and 5-FUR inhibited the colony formation at concentrations ranging from 0.01 to 0.1 microM, whereas 1-100 microM was needed for the cytotoxicity of 5-FU and 5-FUDR. By exposure for 24-48 h, all these drugs inhibited cell growth and caused accumulation of the cells in S or G2 phase at almost the same concentrations of 0.32-8 microM. These results suggest that the cytotoxic effects of UK-21 and 5-FUR are irreversible, while those of 5-FU and 5-FUDR are reversible. To confirm this, KB cells were treated with UK-21 and/or 5-FU for 1 h, and continued to be cultured for 1-7 days, resulting in the inhibition of the cell growth by UK-21 in a dose-dependent manner at concentrations of 10-100 microM, but not by 5-FU even at 100 microM. UK-21, 5-FUR and 5-FU showed a linear relationship between exposure time and IC50 in the colony formation assay with a slope of almost -1, but 5-FUDR did not, suggesting that UK-21, 5-FUR and 5-FU are cell cycle non-specific inhibitors, while 5-FUDR is a cell cycle-specific inhibitor. UK-21 and 5-FUR, but not 5-FU and 5-FUDR inhibited the incorporation of [3H]uridine into the acid insoluble fraction, while UK-21 and 5-FUDR, but not 5-FUR and 5-FU inhibited the incorporation of [3H]thymidine. These results suggest that irreversible cytotoxic effects of UK-21 like 5-FUR are exerted through inhibition of RNA synthesis.

Antimetabolites, Antineoplastic↗
PubMed2003

Cell cycle alterations in the blastoid variant of mantle cell lymphoma (MCL-BV) as detected by gene expression profiling of mantle cell lymphoma (MCL) and MCL-BV.

Overexpression of cyclin D1 is necessary but by itself insufficient for the development of mantle cell lymphoma (MCL). To identify pathways in the pathogenesis of MCL and the blastoid variant (MLC-BV), we compared the gene-expression profiles of microdissected normal mantle cells, MCL, and MCL-BV by oligonucleotide microarrays and quantitative reverse transcriptase PCR (QRT-PCR). We identified and confirmed the overexpression of several genes in MCL-BV that are involved in the cell cycle control at the G1/S and G2/M checkpoints or inhibit apoptotic cell death. The highly expressed cyclin dependent kinase 4 (CDK4) is a cell cycle kinase that associates with cyclin D1 for the progression through the G1/S checkpoint, whereas overexpression of cdc28 protein kinase 1 (CKS1) blocks the inhibition of the cyclin D1/CDK4 complex by the CDK inhibitor p27/Kip1. Other highly expressed genes in MCL-BV that promote the cells through the G1/S-checkpoint include the oncogenes B-Myb, PIM1, and PIM2, and passage through the G2/M-checkpoint is enhanced by high levels of cdc25B. Furthermore, two highly expressed genes that inhibit apoptosis are defender against cell death (DAD1) and RSK1. In summary, our microarray and QRT-PCR analyses identified several candidate genes whose expression increased when comparing normal follicular mantles with MCL and MCLBV, suggesting a potential pathogenic role in the evolution of MCL-BV.

Cell Cycle↗
PubMed1995

Identification of biclonal (duplex) leukaemic cells expressing either CD4+/CD8- or CD4-/CD8+ from a patient with adult T-cell leukaemia/lymphoma.

A 24-year-old Japanese woman was admitted to our hospital in 1987 with a chief complaint of skin eruptions, and was diagnosed as having chronic ATLL. In 1993 the leucocyte count increased gradually to 126.0 x 10(9)/l with 91.5% abnormal lymphocytes expressing two different types of antigenicity, either CD+/CD8- or CD4-/CD8+. Monoclonal integration of human T-cell lymphotropic virus type-I proviral DNA was detected at different sites of the genomic DNA in each cell type. These studies clearly indicate that CD4+/CD8- and CD4-/CD8+ leukaemic cells originated from two independent clones.

Adult↗
PubMed1984

Spontaneous differentiation in the colonies of a nullipotent embryonal carcinoma cell line (F9).

Experiments were undertaken to reveal the spontaneous differentiation capacity of the nullipotent F9 embryonal-carcinoma (EC) cell line in colonies derived from single cells. Culture conditions which allowed the development of neuroblasts in colonies of the multipotent EC cell line (PCC3) were worked out, and comparative studies on neuroblast differentiation in PCC3 and F9 colonies were conducted. Neural-cell-specific silver impregnation, selective staining of cells having electrically excitable membranes with merocyanine 540 and the observation of nerve processes were considered as differentiation markers. The appearance of neuroblasts in F9 and PCC3 colonies could be detected from the 6th day after seeding. The development of neuroblasts was less prevalent in high-density cultures, especially in the case of F9. By the 8th day in differentiating colonies, PCC3 cells lost much of their colony-forming activity, while F9 cells preserved their original high plating efficiency, in spite of advanced differentiation. The determination of growth parameters during differentiation in colonies led to the conclusion that F9 cells had lost certain growth-control mechanisms which normally restrict the clonal growth of EC cells. It is suggested that the phenomenon of nullipotence may be analysed in terms of the coordinated regulation of proliferation and differentiation of EC cells.

Animals↗
PubMed1985

Derivation of a nondifferentiating clone from multipotential PSA1 embryonal carcinoma cells.

The ability of PSA1 embryonal carcinoma cells to differentiate when grown as clones on a monolayer of feeder cells was assessed using morphological criteria. The first appearance of a differentiated phenotype within a clone occurred at different times for individual clones after 10 days of culture, this being apparently unrelated to clone size or cell density. Those clones which showed no morphological evidence of differentiation after several weeks (about 5% of the clones observed) were selected and recloned with the aim of finding variant lines which were stably deficient in their differentiating ability. Undifferentiated clones - identified and selected after about 3 weeks of growth - were of three different types after recloning: those similar to control cultures of PSA1, those having delayed and reduced differentiation frequency, and those having variable frequencies of differentiation in replicate reclonings. The isolation of a variant with a more complete differentiation deficiency was accomplished by selecting ten nondifferentiating clones growing isolated in individual culture wells after 5 weeks of culture. One of these, T2H9, proved to be a stable, differentiation-deficient variant subline with less than 3% of its clones showing any morphological evidence of differentiation in five repeated reclonings. It was also determined that the frequency of undifferentiated clones in embryonal carcinoma cultures increased from 0.3% to 54% after 11 months of in vitro aging, i.e., approximately 200 cell doublings. The isolation of clonal embryonal carcinoma cell derivatives which are stable, heritable differentiation variants provides resources for somatic-cell genetic analysis of stem-cell pluripotency.

Animals↗
PubMed1987

Induction of differentiation of murine embryonal carcinoma cells by ouabain.

Murine embryonal carcinoma cells (EC) can be induced to differentiate by a variety of chemical agents, including retinoid acid (RA) and dimethyl acetamide (DMA). However, it is not known how these agents exert their effects. In this study we demonstrate that murine EC cells can also be induced to differentiate by ouabain at concentrations which inhibit Na+, K+-ATPase activity as measured by inhibition of 86Rb+ uptake. Since the pharmacologic action of ouabain is thought to be specific, we investigated the role of Na+, K+-ATPase inhibition and specific metabolic consequences of this inhibition in the induction of EC differentiation, and explored whether this might be a common mode of action for a variety of structurally diverse inducers. Although the Na+, K+-ATPase maintains ion gradients in cells, our studies failed to demonstrate a consistent role for alterations of ion flux or ion concentration on the differentiation process. Ouabain inhibited cell growth, but a direct correlation between the degree of growth inhibition and the extent of differentiation could not be demonstrated. There was also no evidence that RA or DMA induces differentiation by inhibiting the Na+, K+-ATPase. The mechanism of ouabain induction may be mediated by some alternative consequence of Na+, K+-ATPase inhibition, but it appears to be specific for that inducer and cannot be generalized to that of other inducers of EC differentiation.

Animals↗